<b>On Cysteine and Cystein Peptides. II. S-Acylcysteines in Peptide Synthesis</b>

Zervas, Leonidas; Photaki, Iphigenia; Ghelis, Nicolaos.

doi:10.1021/ja00892a027

Cited by 83 publications

(23 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Synthesis of Thiocholine (TC): [35] 246 mg (1.24 mmol) of acetylthiocholine chloride was added to a round bottom flask to which was added 10 mL of dry methanol. The mixture was degassed under argon for 15 min before 1.1 mL of 2 m NaOH was added to make a final concentration of approximately 0.18 m. The mixture was left to stir for 40 min after which a white precipitate was observed.…”

Section: Methodsmentioning

confidence: 99%

Some More Observations on the Unique Electrochemical Properties of Electrode–Monolayer–Nanoparticle Constructs

et al. 2010

View full text Add to dashboard Cite

Physical and electrochemical properties of gold nanoparticle-based electrodes are highlighted. Polycrystalline gold electrodes are passivated by a self-assembled monolayer, then the immobilization of gold nanoparticles "switch on" the electrochemical reactivity of ruthenium. Herein, gap-mode Raman studies show that the location of the nanoparticles is on the top of the monolayer, meaning that the "switching on" cannot be attributed to a direct electrical contact between nanoparticles and the gold support. This "switching on" feature is also not affected by the size of the gold nanoparticles with a range of diameters between 4 and 67 nm. Further, the charge of the nanoparticles is investigated by grafting chemical groups onto the nanoparticles which is observed to alter the electron-transfer kinetics. The variation in rate constant however is insufficient to attribute the "switching on" phenomenon to a possible adsorption of the redox species onto the nanoparticles.

show abstract

Section: Methodsmentioning

confidence: 99%

Some More Observations on the Unique Electrochemical Properties of Electrode–Monolayer–Nanoparticle Constructs

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Acid (À)-20 was transformed in situ into its corresponding acid chloride with (COCl) 2 , then the amine was added to produce amide ()-21. Treatment with AcOH gave the 2-substituted imidazo [4,5- [26]. The isolated yield of 73% was much higher than that obtained pursuing the Bndeprotection route (see Sect.…”

mentioning

confidence: 90%

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Sahli

Frank

Schweizer

et al. 2005

Helvetica Chimica Acta

View full text Add to dashboard Cite

A new class of nonpeptidic inhibitors of the Zn II -dependent metalloprotease neprilysin with IC 50 values in the nanomolar activity range (0.034 ± 0.30 mm) were developed based on structure-based de novo design (Figs. 1 and 2). The inhibitors feature benzimidazole and imidazo [4,5-c]pyridine moieties as central scaffolds to undergo H-bonding to Asn542 and Arg717 and to engage in favorable p-p stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the Zn II ion and an aryl residue to occupy the hydrophobic S1' pocket, but lack a substituent for binding in the S2' pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds ()-1, ()-2, ()-25, and ()-26 were accomplished using Evans auxiliaries (Schemes 2, 4, and 5). The inhibitors ()-2 and ()-26 with an imidazo[4,5-c]pyridine core are ca. 8 times more active than those with a benzimidazole core (()-1 and ()-25) ( Table 1). The predicted binding mode was established by X-ray analysis of the complex of neprilysin with ()-2 at 2.25-resolution (Fig. 4 and Table 2). The ligand coordinates with its sulfanyl residue to the Zn II ion, and the benzyl residue occupies the S1' pocket. The 1H-imidazole moiety of the central scaffold forms the required H-bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes p-p stacking with the side chain of His711 as well as edge-to-face-type interactions with the side chain of Trp693. According to the X-ray analysis, the substantial advantage in biological activity of the imidazopyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N-atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1' pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors.1. Introduction. ± In the preceding paper [1], we described a new class of inhibitors of the metalloprotease neprilysin with a central 1H-imidazole platform, featuring IC 50 values (IC 50 : concentration of inhibitor at which 50% V max is observed) in the low micromolar range. The de novo design of these compounds was based on the X-ray crystal structure of NEP complexed with phosphoramidon (Protein Data Bank (PDB) file name 1DMT) [2]. For the design of the second-generation inhibitors, we reverted to an unpublished X-ray crystal structure [3] of NEP complexed with the inhibitor thiorphan [4]. During the analysis, we carefully compared the active sites of the two

show abstract

“…4). Thiol and imidazole deprotection in one step with NaOMe in MeOH under H 2 [49], followed by addition of CF 3 COOH, and subsequent treatment of the crude product with methanolic HCl and purification by reverse-phase column chromatography afforded the hydrochloride salts of lead structure (AE)-1 and its diastereoisomer (AE)-43, respectively (Scheme 6). (Table; for a description of the assay, see Exper.…”

Section: Synthetic Approach Towards Leadmentioning

confidence: 99%

A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a Central Imidazole Scaffold

Sahli

Stump

Welti

et al. 2005

Helvetica Chimica Acta

View full text Add to dashboard Cite

Neprilysin (NEP; neutral endopeptidase EC 3.4.24.11) is a Zn II -dependent, membrane-bound endopeptidase. NEP is widely distributed in the organs, particularly in the kidneys and lungs, and it is involved in the metabolism of a number of smaller regulatory peptides. Inhibition of NEP has been proposed as a potential target for analgesic and antihypertensive therapies. In this study, new nonpeptidic inhibitors of neprilysin ((AE)-1, (AE)-43, (AE)-45, and (AE)-46; Table) were designed, based on the X-ray crystal structure of NEP complexed to phosphoramidon (Fig. 1). They feature an imidazole ring as the central scaffold, acting as a peptide bond isoster to undergo H-bonding with the side chains of Asn542 and Arg717 (Fig. 2). The scaffold is decorated with a thiol group to ligate to the Zn II ion and two aromatic residues to bind into the hydrophobic S1' and S2' pockets. The synthesis of the new inhibitors was approached by two routes (Schemes 1 ± 4 and 5 ± 8), with the second one involving a double directed ortho-metallation of the imidazole platform and a Stille cross-coupling, providing the desired target molecules as hydrochloride salts. In a fluorescence assay, inhibitors (AE)-1, (AE)-43, (AE)-45, and (AE)-46 all exhibit IC 50 values in the single-digit micromolar activity range (2 ± 4 mm, Table), which validates the binding mode postulated by modeling. Useful guidelines for a next lead optimization cycle were obtained in several control runs.

show abstract

On Cysteine and Cystein Peptides. II. S-Acylcysteines in Peptide Synthesis

Cited by 83 publications

References 0 publications

Some More Observations on the Unique Electrochemical Properties of Electrode–Monolayer–Nanoparticle Constructs

Some More Observations on the Unique Electrochemical Properties of Electrode–Monolayer–Nanoparticle Constructs

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a Central Imidazole Scaffold

Contact Info

Product

Resources

About